Process of producing bleach boosters

ABSTRACT

This invention relates to a process of producing compounds, which are useful as bleach boosters, as well as to the compounds, which are obtainable using said process, and to their use.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a divisional application based on U.S.application Ser. No. 11/917,217 filed Dec. 12, 2007, now U.S. Pat. No.8,129,531, which published on Sep. 4, 2008, as US 2008/0214819 A1, asthe national stage of international application PCT/EP2006/063238, filedon Jun. 14, 2006, claiming benefit to the filing date of European Appl.No. 2005 013129.1 and 2005 013134.1, both filed on Jun. 17, 2005. All ofthe above applications are hereby incorporated by reference in theirentirety.

This invention relates to a process of producing compounds, which areuseful as bleach boosters, as well as to the compounds, which areobtainable using said process, and to their use.

Oxygen bleaching agents, for example hydrogen peroxide, are typicallyused to facilitate the removal of stains and soils from clothing andvarious surfaces. Unfortunately such agents are extremely temperaturerate dependent. As a result, when such agents are employed in coldersolutions, the bleaching action of such solutions is markedly decreased.

In an effort to resolve the aforementioned performance problem, theindustry developed a class of materials known as “bleach activators” or“bleach boosters”, with both terms being used identical. However, assuch materials rapidly lose their effectiveness at solution temperaturesof less than 40° C., new organic catalysts such as3,4-dihydro-2-[2-(sulfooxy)decyl]isoquinolimium, inner salt weredeveloped. The term “organic catalyst” is used as another term for“bleach activator” or “bleach booster” throughout this description. Ingeneral, while such current art catalysts are effective in lowertemperature water conditions, they can inactivate certain enzymes. Asmost laundry and cleaning compositions are formulated with enzymes,formulating cleaning products with such catalysts can be problematic.

Accordingly, there is a need for an organic catalyst that can providethe combined benefits of formulation flexibility, low water temperaturebleaching performance and enzyme compatibility.

The process of producing1-(4,4-dimethyl-3,4-dihydroisochinoline)decane-2-sulfate, which is knownto be a bleach booster, is described in WO 01/16273:

1,2-decanediol is dissolved in carbon tetrachloride. Thionyl chloride isadded dropwise at room temperature and the reaction mixture is heated to60° C. After some h time the reaction mixture is cooled using an icebath. Water and acetonitrile are added as well as ruthenium chloridehydrate and sodium periodate. After stirring for an hour at roomtemperature, the reaction mixture is extracted with diethylether (4times); the organic layers are subsequently washed with water (5 times),saturated sodium bicarbonate (3 times), brine (2 times), filteredthrough celite/silica gel, and dried over magnesium sulphate. After thatthe resulting liquid is concentrated to yield a clear oil, which oil is1,2-decanediol cyclic sulphate. In the next reaction step4,4-dimethyl-3,4-dihydroisoquinoline and acetonitrile are combined withthe 1,2-decanediol cyclic sulphate, which is added in one portion. Afteranother addition of acetonitrile the reaction mixture is stirred forsome h. Then the precipitate is collected, washed with acetone andallowed to dry to give1-(4,4-dimethyl-3,4-dihydroisochinoline)decane-2-sulfate.

While this process can be used in laboratory scale there exists a strongneed to have a process that is usable in industrial scale, i.e. aprocess, which avoids the use of expensive educts such as thionylchloride. Therefore it is one goal of the present invention to find aprocess, which avoids the use of thionyl chloride. It is another goal ofthe present invention to find new compounds, which are accessible usingthis process and which compounds can be used as bleach boosters,preferably those bleach boosters having the combined benefits as areoutlined above.

Surprisingly it has been found that these needs are met by the compoundsaccording to embodiments 1 to 6 and the process according to embodiments7 to 22, as follows:

1.) Compound of formula (I) or (II)

-   -   wherein R¹, R² and G independently from each other are selected        from    -   R¹═H, C₁-C₂₀-alkyl, C₁-C₂₀-cycloalkyl, C₁-C₂₀-aryl or        C₂-C₂₀-aralkyl,    -   R²═C₁C₂₀-alkyl, C₁-C₂₀—cycloalkyl, C₁-C₂₀-aryl or C₁-C₂₀-aralkyl        and    -   G=-O—, —CH₂O—, —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—,        —(CH₂)₆—, —(CH₂)₇—, —(CH₂)₈—.

2.) Compound according to embodiment 1, wherein

-   -   R¹, R² and G independently from each other are selected from    -   R¹═H, C₁-C₁₂-alkyl, C₁-C₁₂-cycloalkyl, C₁-C₁₂-aryl or        C₁-C₁₂-aralkyl,    -   R²═C₁-C₁₂-alkyl, C₁-C₁₂-cycloalkyl, C₁-C₁₂-aryl or        C₁-C₁₂-aralkyl and    -   G=-O—, —CH₂O—, —(CH₂)₂—, —CH₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—.

3.) Compound according to embodiment 1 or 2, wherein

-   -   R¹, R² and G independently from each other are selected from    -   R¹═H, C₁C₄-alkyl, C₁C₆-cycloalkyl, C₁C₈-aryl or C₁C₈-aralkyl,    -   R²═C₁C₄-alkyl, C₁C₆-cycloalkyl, C₁C₈-aryl or C₁C₈-aralkyl and    -   G=-CH₂—.

4.) Compound according to any one of embodiment 1, 2 or 3, wherein G isselected from the group consisting of: n-butyl, n-pentyl, cyclopentyl,n-hexyl, cyclohexyl, n-heptyl, cyclohexylmethyl, n-octyl, benzyl,2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 4-ethylbenzyl,4-iso-proylbenzyl and 4-tert-butyl-benzyl.

5.) Compound according to any one of embodiments 1 to 4, having anenzyme compatibility value of 70 or greater.

6.) Compound according to embodiment 5, having an enzyme compatibilityvalue of 80 or greater.

7.) Process comprising the following steps:

-   -   bisalkylation of a benzene cyanide,    -   reduction of the nitrile obtained in step a) to give an amine,    -   amidification of the amine obtained in step b),    -   ring closure of the product obtained in step c),    -   quaternation of the product obtained in step d).

8.) Process according to embodiment 7, wherein in step a) analkylchloride, -bromide, -iodide or -tosylate or a substitutedarylchloride, -bromide, -iodide or -tosylate is used in amount of 2 to 4equivalents based on benzylcyanide.

9.) Process according to embodiment 8, wherein in step a) analkylchloride or substituted benzylchloride is used in amount of 2 to2.5 equivalents based on benzylcyanide.

10.) Process according to embodiment 7 to 9, wherein the reaction ofstep a) takes place in the presence of 2 to 4 equivalents (based onbenzylcyanide) of a base.

11.) Process according to embodiment 10, wherein the base is KOtBu orKOH/tBuOH.

12.) Process according to any one of embodiments 7 to 11, whereinsolvent, alkylating agent and benzylcyanide are first mixed and thereaction is initiated by addition of the base.

13.) Process according to any one of embodiments 7 to 12, wherein stepb) is performed using hydrogen in the presence of a catalyst.

14.) Process according to any one of embodiments 7 to 13, wherein stepc) is performed using formic acid and/or formic acid ester.

15.) Process according to any one of embodiments 7 to 14, wherein stepd) is performed using phosphorous pentoxide and an acid.

16.) Process according to embodiment 15, wherein the acid is selectedfrom the group consisting of poly phosphorous acid, trifluormethaneacid,formic acid and methane sulfonic acid.

17.) Process according to embodiment 15 or 16, wherein the reactionmixture of step d) is neutralized using KOH.

18.) Process according to any one of embodiments 7 to 17, wherein instep d) after neutralization the amine is oxidized to give an imineusing sodium hypochlorite.

19.) Process according to any one of embodiments 7 to 18, wherein instep the alkylating agent is used in an amount of 1 to 1.2 equivalentsbased on the product from step d).

20.) Process according to any one of embodiments 7 to 19 wherein in atleast one of steps a) to e) a solvent is used.

21.) Process according to embodiment 20, wherein the same solvent isused in more than one step.

22.) Process according to embodiment 20 or 21, wherein the solvent istoluene.

As used herein, the term “cleaning composition” includes, unlessotherwise indicated, granular or powder-form all-purpose or “heavy-duty”washing agents, especially laundry detergents; liquid, gel or paste-formall-purpose washing agents, especially the so-called heavy-duty liquidtypes; liquid fine-fabric detergents; hand dishwashing agents or lightduty dishwashing agents, especially those of the high-foaming type;machine dishwashing agents, including the various tablet, granular,liquid and rinse-aid types for household and institutional use; liquidcleaning and disinfecting agents, including anti-bacterial hand-washtypes, laundry bars, mouthwashes, denture cleaners, car or carpetshampoos, bathroom cleaners; hair shampoos and hair-rinses; shower gelsand foam baths and metal cleaners; as well as cleaning auxiliaries suchas bleach additives and “stain-stick” or pre-treat types.

As used herein, the phrase “is independently selected from the groupconsisting of . . . ” means that moieties or elements that are selectedfrom the referenced Markush group can be the same, can be different orany mixture of elements.

The test methods disclosed in the Test Methods Section of the presentapplication must be used to determine the respective values of theparameters of Applicants' inventions.

Unless otherwise noted, all component or composition levels are inreference to the active level of that component or composition, and areexclusive of impurities, for example, residual solvents or by-products,which may be present in commercially available sources.

All percentages and ratios are calculated by weight unless otherwiseindicated. All percentages and ratios are calculated based on the totalcomposition unless otherwise indicated.

It should be understood that every maximum numerical limitation giventhroughout this specification includes every lower numerical limitation,as if such lower numerical limitations were expressly written herein.Every minimum numerical limitation given throughout this specificationwill include every higher numerical limitation, as if such highernumerical limitations were expressly written herein. Every numericalrange given throughout this specification will include every narrowernumerical range that falls within such broader numerical range, as ifsuch narrower numerical ranges were all expressly written herein.

All documents cited are, in relevant part, incorporated herein byreference; the citation of any document is not to be construed as anadmission that it is prior art with respect to the present invention.

A Compound of formula (I) or (II)

wherein R¹, R² and G independently from each other are selected fromR¹═H, C₁-C₂₀-alkyl, such as C₁-, C₂-, C₃-, C₄-, C₅-, C₆-, C₁₉-,C₂₀-alkyl, C₁-C₂₀-cy-cloalkyl, such as, C₅-, C₆-, C₇-, C₈-, C₁₉-,C₂₀-cycloalkyl, C₁-C₂₀-aryl, such as C₅-, C₆-, C₇-, C₈-, C₁₉-, C₂₀-arylor C₁-C₂₀-aralkyl,R²═C₁-C₂₀-alkyl, C₁-C₂₀-cycloalkyl, C₁-C₂₀-aryl or C₁-C₂₀-aralkyl andG=-O—, —CH₂O—, —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—,—(CH₂)₇—, —(CH₂)₈— forms an object of the present invention.

A compound as mentioned above, wherein

R¹, R² and G independently from each other are selected from

R¹═H, C₁-C₁₂-alkyl, C₁-C₁₂-cycloalkyl, C₁-C₁₂-aryl or C₁-C₁₂-aralkyl,

R²═C₁-C₁₂-alkyl, C₁-C₁₂-cycloalkyl, C₁-C₁₂-aryl or C₁-C₁₂-aralkyl and

G=-O—, —CH₂O—, —(CH₂)₂—, —CH₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅— ispreferred.

A compound as mentioned above, wherein

R¹, R² and G independently from each other are selected from

R¹═H, C₁-C₄-alkyl, C₁-C₆-cycloalkyl, C₁-C₈-aryl or C₁-C₈-aralkyl,

R²═C₁-C₄-alkyl, C₄-C₈-alkyl, C₁-C₆-cycloalkyl, C₁-C₈-aryl orC₁-C₈-aralkyl and

G=-CH₂— is more preferred.

A compound as mentioned above, wherein

G is selected from the group consisting of: n-butyl, n-pentyl,cyclopentyl, n-hexyl, cyclohexyl, n-heptyl, cyclohexylmethyl, n-octyl,benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 4-ethylbenzyl,4-iso-propylbenzyl and 4-tert-butylbenzyl forms a particularly preferredembodiment of the present invention.

Suitable C₁-C₄ alkyl moieties include, but are not limited to methyl,ethyl, iso-propyl, and tert-butyl. Those compounds in which at least oneof R¹, R² is methyl, ethyl, iso-propyl, and tert-butyl are preferred.

Each R² preferably is independently selected from C₄-C₈ alkyl,C₁-C₁₂-cycloalkyl, benzyl, 2-methylbenzyl, 3-methylbenzyl,4-methylbenzyl, 4-ethylbenzyl, 4-iso-propylbenzyl and4-tert-butylbenzyl. Suitable C₄-C₈ alkyl moieties include, but are notlimited to n-butyl, n-pentyl, n-hexyl, n-heptyl and octyl.C₁-C₁₂-cycloalkyl includes cyclohexyl, cyclopentyl, cyclohexylmethyl.

In one aspect of the invention G is selected from —O— and —CH₂—. R¹ isselected from H, methyl, ethyl, iso-propyl, and tert-butyl. Each R² isindependently selected from C₄-C₆ alkyl, benzyl, 2-methylbenzyl,3-methylbenzyl, and 4-methylbenzyl.

In one aspect of the invention G is —CH₂—, R¹ is H and each R² isindependently selected from n-butyl, n-pentyl, n-hexyl, benzyl,2-methylbenzyl, 3-methylbenzyl, and 4-methylbenzyl.

Surprisingly it was found that the compounds of the present inventionlead to better low water temperature bleaching performance, when used ina cleaning composition.

In addition to that the unexpected effect of good enzyme compatibilitywas found. Applicants have found that judicious selection of the R¹ andR² moieties of the organic catalyst of the present invention results inimproved enzyme compatibility. While not being bound by theory,Applicants believe this is due to favourable partitioning of thecatalyst in aqueous environments as a result of the aforementionedjudicious selection of the said moieties.

In one aspect of Applicants' invention, the organic catalyst has anenzyme compatibility value of 70 or greater, or even 80 or greater.Typical enzymes that are used in cleaning compositions include, but arenot limited to, hemicellulases, peroxidases, proteases, cellulases,xylanases, lipases, phospholipases, esterases, cutinases, pectinases,mannanases, pectate lyases, keratinases, reductases, oxidases,phenoloxidases, lipoxygenases, ligninases, pullulanases, tannases,pentosanases, malanases, β-glucanases, arabinosidases, hyaluronidase,chondroitinase, laccase, and amylases, or mixtures thereof.

Cleaning compositions and cleaning composition additives comprising thecompounds described in detail above may be advantageously employed forexample, in laundry applications, hard surface cleaning, automaticdishwashing applications, as well as cosmetic applications such asdentures, teeth, hair and skin. However, due to the unique advantages ofboth increased effectiveness in lower temperature solutions and thesuperior enzyme compatiblity, the organic catalysts of the presentinvention are ideally suited for laundry applications such as thebleaching of fabrics through the use of bleach containing detergents orlaundry bleach additives. Furthermore, the organic catalysts of thepresent invention may be employed in both granular and liquidcompositions.

The organic catalysts of the present invention may also be employed in acleaning additive product. While the additive product may be, in itssimplest form, Applicants' organic catalyst, a cleaning additive productincluding the organic catalysts of the present invention is ideallysuited for inclusion in a wash process when additional bleachingeffectiveness is desired. Such instances may include but are not limitedto, low temperature solution cleaning application.

Cleaning compositions and cleaning additives require a catalyticallyeffective amount of Applicants' organic catalyst. The required level ofsuch catalyst may be achieved by the addition of one or more species ofApplicants' organic catalyst. As a practical matter, and not by way oflimitation, the compositions and cleaning processes herein can beadjusted to provide on the order of at least 0.001 ppm, from about 0.001ppm to about 500 ppm, from about 0.005 ppm to about 150 ppm, or evenfrom about 0.05 ppm to about 50 ppm of Applicants' organic catalyst inthe wash liquor. In order to obtain such levels in the wash liquor,typical compositions herein may comprise from about 0.0002% to about 5%,or even from about 0.001% to about 1.5%, of organic catalyst, by weightof the cleaning compositions.

When the Applicants' organic catalyst is employed in a granularcomposition, it may be desirable for the Applicants' organic catalyst tobe in the form of an encapsulated particle to protect the Applicants'organic catalyst from moisture and/or other components of the granularcomposition during storage. In addition, encapsulation is also a meansof controlling the availability of the Applicants' organic catalystduring the cleaning process and may enhance the bleaching performance ofthe Applicants' organic catalyst. In this regard, the Applicants'organic catalyst can be encapsulated with any encapsulating materialknown in the art.

The encapsulating material typically encapsulates at least part,preferably all, of the Applicants' organic catalyst. Typically, theencapsulating material is water-soluble and/or water-dispersible. Theencapsulating material may have a glass transition temperature (Tg) of0° C. or higher.

The encapsulating material is preferably selected from the groupconsisting of carbohydrates, natural or synthetic gums, chitin andchitosan, cellulose and cellulose derivatives, silicates, phosphates,borates, polyvinyl alcohol, polyethylene glycol, paraffin waxes andcombinations thereof. Preferably the encapsulating material is acarbohydrate, typically selected from the group consisting ofmonosaccharides, oligosaccharides, polysaccharides, and combinationsthereof. Most preferably, the encapsulating material is a starch.Preferred starches are described in EP 0 922 499; U.S. Pat. No.4,977,252; U.S. Pat. No. 5,354,559 and U.S. Pat. No. 5,935,826.

The encapsulating material may be a microsphere made from plastic suchas thermoplastics, acrylonitrile, methacrylonitrile, polyacrylonitrile,polymethacrylonitrile and mixtures thereof; commercially availablemicrospheres that can be used are those supplied by Expancel ofStockviksverken, Sweden under the trademark Expancel®, and thosesupplied by PQ Corp. of Valley Forge, Pa. USA under the tradename PM6545, PM 6550, PM 7220, PM 7228, Extendospheres®, Luxsil®, Q-Cel® andSphericel®.

The cleaning compositions herein will preferably be formulated suchthat, during use in aqueous cleaning operations, the wash water willhave a pH of between about 6.5 and about 11, or even about 7.5 and 10.5.Liquid dishwashing product formulations may have a pH between about 6.8and about 9.0. Laundry products typically have a pH of from about 9 toabout 11. Techniques for controlling pH at recommended usage levelsinclude the use of buffers, alkalis, acids, etc., and are well known tothose skilled in the art.

While not essential for the purposes of the present invention, thenon-limiting list of adjuncts illustrated hereinafter are suitable foruse in the instant compositions and may be desirably incorporated incertain embodiments of the invention, for example to assist or enhancecleaning performance, for treatment of the substrate to be cleaned, orto modify the aesthetics of the cleaning composition as is the case withperfumes, colorants, dyes or the like. The precise nature of theseadditional components, and levels of incorporation thereof, will dependon the physical form of the composition and the nature of the cleaningoperation for which it is to be used. Suitable adjunct materialsinclude, but are not limited to, surfactants, builders, chelatingagents, dye transfer inhibiting agents, dispersants, enzymes, and enzymestabilizers, catalytic materials, bleach activators, hydrogen peroxide,sources of hydrogen peroxide, preformed peracids, polymeric dispersingagents, clay soil removal/anti-redeposition agents, brighteners, sudssuppressors, dyes, perfumes, structure elasticizing agents, fabricsofteners, carriers, hydrotropes, processing aids, solvents and/orpigments. In addition to the disclosure below, suitable examples of suchother adjuncts and levels of use are found in U.S. Pat. Nos. 5,576,282,6,306,812 B1 and 6,326,348 B1 that are incorporated by reference.

The cleaning compositions can be formulated into any suitable form andprepared by any process chosen by the formulator, non-limiting examplesof which are described in Applicants' examples and in U.S. Pat. No.5,879,584; U.S. Pat. No. 5,691,297; U.S. Pat. No. 5,574,005; U.S. Pat.No. 5,569,645; U.S. Pat. No. 5,565,422; U.S. Pat. No. 5,516,448; U.S.Pat. No. 5,489,392; U.S. Pat. No. 5,486,303 all of which areincorporated herein by reference.

Organic Catalyst/Enzyme Compatibility Test

The test described below uses an alpha amylase activity assay to measurethe impact of organic catalysts on the enzyme.

Equipment. UV/Vis spectrophotometer capable of measuring @ 415 nm,heated magnetic stirrer capable of 40° C., 5 ml Luer lock syringe andfilters (Acrodisc 0.45

μm), pH meter, and balance (4-place analytical).

Reagents. Merck Amylase Kit (Merck Eurolab, Cat. No. 1.19718.0001);Trizma Base (Sigma Cat # T-1503, or equivalent); Calcium ChlorideDihydrate (Sigma Cat # C-5080, or equivalent); Sodium ThiosulfatePentahydrate (Sigma Cat # S-6672 or equivalent); Hydrochloric Acid (VWRCat # JT9535-0, or equivalent); Hardness solution (CTC Group, 3.00 gr/ccor equivalent); Sodium Percarbonate; Peracetic Acid (Aldrich, Cat.#26933-6 or equivalent); Amylase enzymes: Termamyl, Natalase, andDuramyl (Novozymes, Denmark); Granular detergent matrix containing noenzyme, organic catalyst or bleaching agents.

1.) Solution Preparation: Prepare the Following:

-   -   a.) TRIS Assay Buffer. Prepare 1 liter of 0.1M TRIS buffer, 0.5%        sodium thiosulphate (W/V), 0.11% calcium chloride (w/v) at pH        8.3.    -   b.) Blank Detergent Solution. Prepare one liter of 0.5% enzyme        and bleach free granular detergent product in deionized water        (W/V) that is 250 ppm H₂O₂ (0.77 gm percarbonate) and 10 gpg        hardness (880 UI of hardness).    -   c.) Termamyl, Duramyl and Natalase Stock. Make 100 ml solutions        each of a 0.1633 mg active Termamyl per ml TRIS Buffer, a 0.1159        mg active Natalase per ml TRIS Buffer, and a 0.1596 mg active        Duramyl per ml TRIS Buffer.    -   d.) Organic catalyst stocks. Make a 500 ppm in methanol solution        of μm.    -   e.) Peracetic acid stock. Make a 3955 ppm peracetic acid        solution in deionized water.    -   f.) Amylase reagent. Follow Merck kit instructions for preparing        flacons (containers) 1 and 2 using flacon 3 and subsequent        mixing of flacons 1 and 2 to produce the final reagent used in        the amylase activity analysis.        2.) Sample Analysis    -   a.) Analysis of sample with enzyme only: Add 100 ml of blank        detergent solution to a 150 ml beaker. Place beaker on heated        stir plate and bring temperature to 40° C. with stirring. Add Y        μl of enzyme stock to the beaker where Y=612 μL for Duramyl, 306        μl for Termamyl, or 918 μl for Natalase. Spike only enzyme of        interest. Stir sample for 1 minute. Start timer. At 7 minutes 45        seconds, pull a sample and filter it using a 0.45 μm syringe        filter (5 ml syringe). Mix 6 μl of filtered sample with 250 μL        of amylase reagent in a cuvette and place the cuvette in a        UV/VIS spectrophotometer and monitor change in absorbance at 415        nm. Determine length of time (t_(E)) to the nearest second        required to obtain an absorbance reading of 1.0 for each enzyme.        Use each enzyme's t_(E) in Steps 2.)b.) and 2.)c.) below.    -   b.) Analysis of sample with enzyme and peracetic acid only.        Follow Step 2.)a.) except after enzyme addition, allow solution        to stir for 1 minute then add 127 μl of peracetic acid stock and        start timer. Pull sample at 7 minutes 45 seconds as in Step        2.)a.). Once sample and reagent are mixed, record the absorbance        at t_(E) for the respective enzyme. Designate such absorbance        A_(b).    -   c.) Analysis of sample with enzyme, peracetic acid, and organic        catalyst. Follow Step 2.)a.) except after enzyme addition, allow        solution to stir for 1 minute then add 127 μl of peracetic acid        stock and 100 μl of organic catalyst stock and start timer. Pull        sample at 7 minutes 45 seconds as in Step 2.)a.). Once sample        and reagent are mixed, record the absorbance at t_(E) for the        respective enzyme. Designate such absorbance A,        3.) Calculate Enzyme Compatibility Value (ECV)    -   a.) Calculate the ECV for each specific enzyme: termamyl        (ECV_(ter)), duramyl (ECV_(dur)) and natalase (ECV_(nat)). The        ECV for any specific enzyme is (A_(c)/A_(b))×100 where A_(b) and        A_(c) are the values determined in Steps 2.)b.) and 2.)c.),        respectively, for that enzyme.    -   b.) The ECV for a given organic catalyst is the average of the        individual ECV values for the three enzymes. Thus,        ECV=(ECV_(ter)+ECV_(dur)+ECV_(nat))/3.    -   The present invention does not only deal with compounds, but        also with processes of producing such compounds. Therefore a    -   process comprising the following steps:    -   a) bisalkylation of a benzene cyanide,    -   b) reduction of the nitrile obtained in step a) to give an        amine,    -   c) amidification of the amine obtained in step b),    -   d) ring closure of the product obtained in step c),    -   e) quaternation of the product obtained in step d)        forms another object of the present invention.

The overall process can be illustrated as follows:

Based on this general process there exist preferred embodiments, one ofwhich is a process, wherein in step a) an alkylchloride, -bromide,-iodide or -tosylate or a substituted arylchloride, -bromide, -iodide or-tosylate is used in amount of 2 to 4 equivalents based onbenzylcyanide. A process wherein in step a) an alkylchloride orsubstituted benzylchloride is used in an amount of 2 to 2.5 equivalentsbased on benzylcyanide is more preferred.

A process as described above, wherein the reaction of step a) takesplace in the presence of 2 to 4 equivalents (based on benzylcyanide) ofa base is another preferred embodiment of the present invention, wherebyit is preferred when the base is KOtBu or KOH/tBuOH and it is alsopreferred when solvent, alkylating agent and benzylcyanide are firstmixed and the reaction is initiated by addition of the base. By doingthis the formation of side products can be reduced.

Possible solvents for the reaction in step a) are toluene,tetrahydrofurane (THF), dimethylsulfoxide (DMSO), dimethylformamide(DMF) and others, with toluene being preferred. The reaction of step a)can be performed at atmospheric pressure as well as under positivepressure or under a light vacuum. The use of a neutral gas is possible.The temperature lies in the range of from −40° C. to 200° C., with arange from 0 to 120° C. being preferred.

A process as described above, wherein step b) is performed usinghydrogen in the presence of a catalyst is preferred. When using aborane-THF-complex numerous side products are obtained. When using acatalyst such as Raney-nickel the appearance of such side products canbe avoided or at least be reduced and the purity of the product isincreased.

Possible solvents for the reaction in step b) again are toluene,tetrahydrofurane (THF), dimethylsulfoxide (DMSO), dimethylformamide(DMF) and others, with toluene being preferred. The reaction of step b)can be performed at about atmospheric pressure as well as under positivepressure, with positive pressure being preferred. The temperature liesin the range of from −40° C. to 200° C., with a range from 0 to 120° C.being preferred.

A process as described above, wherein step c) is performed using formicacid and/or formic acid ester forms another preferred embodiment of thepresent invention, with the use of formic acid ester being preferred. Itis particularly preferred to use formic acid methyl ester, since it hasa boiling point of 34° C., which makes the removal of a surplus easiercompared to formic acid having a boiling point of 100° C. The reactionof step c) can advantageously be performed at a temperature of aboutroom temperature. In any case it should be performed below the boilingtemperature of the components. By increasing the pressure, whichnormally is atmospheric pressure, also the temperature can be increased,which leads to a reduction of the time needed for the completion of thereaction.

Step d) can be performed using a Bischler-Napieralski reaction:

A process as described above, wherein step d) is performed usingphosphorous pentoxide and an acid is another preferred object of thepresent invention, whereby it is preferred when the acid is selectedfrom the group consisting of poly phosphorous acid, trifluoro methaneacid, formic acid and methane sulfonic acid. Compared to standardBischler-Napieralski reaction conditions the amount ofphosphor-containing compounds as well as the reaction time could bereduced. This makes the reaction less expensive and has a positiveeffect with respect to the overall environmental rating of the process.Instead of poly phosphorous acid (PPA) methane sulfonic acid (MSA) canbe used. This is not possible when using MSA alone. At temperatures ofabout 160° C., which is above the decomposition temperature of MSA,which is about 140° C., good results can be obtained.

It is further preferred when in the process as described above thereaction mixture of step d) is neutralized using KOH, because this leadsto salts that have a higher solubility.

An alternative for this step is

to perform a Pictet-Spengler reaction from (4) to (13), followed bycleavage of the amide to give (14) and subsequent oxidation using sodiumhypochlorite. A great advantage of this alternative is to be seen in thefact that the reaction can be performed as a one pot reaction. Anadditional advantage is the fact, that this is a phosphate free route toobtain the desired products, which means lower cost for waste disposaland an environmentally friendly process.

As a source of formaldehyde trioxane is advantageous, since it has amelting point of 62° C., and therefore can be applied easily as aliquid. It is obvious that a heated feed pipe can advantageously beenused. As the acid all kinds of strong acids, such as trifluoro aceticacid, formic acid or methane sulfonic acid can be used.

A process as described above, wherein in step d) after neutralizationthe amine is oxidized to give an imine using sodium hypochlorite ispreferred and it is even more preferred when in this step the alkylatingagent is used in an amount of 1 to 1.2 equivalents based on the productfrom step d):

It is particularly preferred, when a process as described above isperformed in which process in at least one of steps a) to e) a solventis used, whereby preferably the same solvent is used in more than onestep.

A process as described above, wherein the solvent is toluene isparticularly preferred and a process wherein the solvent in steps a) tod) is toluene and in step e) is acetone or acetonitrile is mostpreferred. Acetone has the additional advantage of having a low boilingpoint—which facilitates the removal of the solvent.

Suitable organic catalysts can be produced using a variety of reactionvessels and processes including batch, semi-batch and continuousprocesses.

The oxaziridinium ring containing version of the aforementioned catalystmay be produced by contacting an iminium containing version of saidcatalyst with an oxygen transfer agent such as a peroxycarboxylic acidor a peroxymonosulfuric acid. Such species can be formed in situ andused without purification.

For a better understanding the present invention is illustrated by thefollowing examples, which are not to be understood as being limiting thescope of the invention, which scope is expressed in the claims:

EXAMPLE 1

-   -   a) In 2 l four necked flask benzylcyanide (118 g, 1.0 mol, 1.0        eq.), 4-methyl-benzylchloride (286 g, 2.0 mol, 2.0 eq.) and        toluene (510 g) were mixed. At 25° C. potassium tert-bu-tylate        (288 g, 2.52 mol, 2.52 eq.) were added while stirring. After        stirring for 3.5 h at 25° C. water (550 g) was added and the        mixture was stirred for another 10 min. Phase separation and        washing of the organic phase with water (200 g) lead—after        removal of the solvent—to bisalkylated benzylcyanide (315 g, 95%        of theory), having a purity of 98% according to gas        chromatography (GC).    -   b) Bisalkylated benzylcyanide (50 g, 0.15 mol, 1.0 eq.) were        dissolved in 50 g of toluene and 10 g Raney-nickel were added.        After hydration in an autoclave for 25 h at a pressure of 65 bar        hydrogen pressure at 100° C. the reaction was completed.        Filtering off the Raney-nickel and removal of the solvent        yielded the desired amine (49 g, 99% of theory) having a purity        of 95% according to GC.    -   c) The primary amine (74 g, 0.22 mol) was treated with formic        acid methyl ester (70 g, 1.17 mol) at a temperature of 25° C.        for 10 h. After removal of the solvent the desired amide was        obtained as a white solid (78 g, 97% of theory).    -   d) Phosphorous pentoxide (33 g, 0.22 mol) and poly phosphorous        acid (114 g) were stirred under nitrogen atmosphere at 150° C.        for 1 h. The amide (78 g, 0.22 mol) was added and the reaction        mixture was stirred for 1 h at 170° C. After cooling to 80° C.        water (150 g) was added, and neutralization was conducted using        KOH (50% ic in water). Addition of tert-butylmethylether (600        ml), phase separation and drying of the organic phase        yielded—after removal of the solvent—the 4,4-disubstituted        dihydroisoquinoline (60 g, 80% of theory) having a purity of 91%        according to GC.    -   e) The 4,4-disubstituted dihydroisoquinoline of step d) (50 g,        91% purity, 0.134 mol, 1.0 eq.) was dissolved in acetonitrile        (280 ml) and propanesulton (18 g, 0.147 mol, 1.1 eq.) were        added. The mixture was stirred for 2 h at a temperature of        50° C. After cooling to 25° C. and addition of        tert-butylmethylether (200 ml) the desired product precipitated.        After drying of the solid the aimed compound was obtained as a        beige powder (47 g, 76% of theory).

EXAMPLE 2 TO 26

The following reaction was performed using various conditions:

with the conditions and results being listed in table 1.

TABLE 1 starting material 13 g benzyl cyanide (1) amount GC [%] Example2 base solvent temperature time 1 6 7 8 2 4eq. 3.26eq KOtBu 78 g DMSO RT20 h  4 20 11 61 3 4eq. 3.26eq KOtBu 78 g THF RT 20 h  15 24 2 58 4 2eq.3.26eq KOtBu 78 g DMSO RT 4 h 87 5 2eq. 3.26eq KOtBu 40 g DMSO RT 4 h 926 2eq. 3.26eq KOtBu 40 g toluene RT 4 h >95 7 2eq. 2eq KOtBu 40 gtoluene RT 4 h 5 10 86 8 2eq. 3.26eq. NaOMe 40 g toluene RT 20 h  13 3832 17 9 2eq. 3.26eq. NaOMe 40 g toluene  60° C. 2 h 11 31 36 22 10 2eq.3.26eq. NaOMe 40 g toluene 100° C. 2 h 11 31 35 23 11 2eq. 3.26eq. NaOMe40 g toluene 100° C. 4 h 17 40 29 7 12 2eq. 3.26eq. NaOMe 40 g THF RT 20h  16 43 29 10 13 2eq. 3.26eq. NaOMe 40 g DMSO RT 4 h 12 33 23 32 142eq. 3.26eq. NaOMe 40 g DMSO 100° C. 4 h 14 19 19 38 15 2eq. 3.26eq.NaOMe 40 g DMSO 100° C. 7 h 15 16 20 40 16 2eq. 3.26eq. NaOMe-solutionnone RT 20 h  26 57 15 2 17 2eq. 3.26eq. NaOMe-solution none  70° C. 2 h16 62 16 6 18 2eq. 3.26eq. NaOMe-solution none  86° C. 2 h 15 59 15 6 192eq. 3.26eq. NaOMe-solution 40 g toluene 100° C. 4 h 24 76 20 2eq.3.26eq. NaOnBu-solution none RT 3 h 20 29 16 21 2eq. 3.26eq.NaOnBu-solution none 100° C. 4 h 12 20 4 22 2eq. 3.26eq. K₂CO₃ 40 g DMF116° C. 2 h 48 38 23 2eq. 3.26eq. K₂CO₃ 40 g toluene 116° C. 2 h 32 62 524 2eq. 3.26eq. K₂CO₃ 40 g DMSO 120° C. 2 h 13 2 32 8 25 2eq. 3.26eq.K₂CO₃ 40 g DMSO  60° C. 2 h 20 46 28 7 26 2eq. 3.26eq. K₂CO₃ 40 g THF 80° C. 4 h 28 58 14

EXAMPLES 27 TO 46

Also the following reaction step was varied:

the conditions and results being listed in table 2 below:

TABLE 2 starting material 30 g (10) GC [%] Example P₂O₅ acid solventtemperature time 10 11 12 27 36 g 200 g PPA none 170° C. 40 min. 99 2818 g 100 g PPA none 170° C. 40 min. 7 91 29 18 g 100 g PPA none 170° C.60 min. 4 95 30 18 g 100 g PPA none 170° C. 60 min. 3 92 4 31 18 g 100 gPPA none 200° C. 60 min. 95 5 32 18 g 100 g PPA none 170° C. 80 min. 492 4 33 18 g 100 g PPA none 170° C. 120 min. 1 94 4 34 18 g 50 g PPA,none 170° C. 40 min. 31 36 1 50 g MSA 35  9 g 50 g PPA none 170° C. 40min. 21 30 20 36  9 g 50 g PPA none 200° C. 40 min. 76 37  9 g 50 g PPAdichloro- 170-180° C.   40 min. 40 34 18 benzene 38 none 1eq. MSAdichloro- 170° C. 60 min. 46 benzene 39 18 g 180 g MSA none 130° C. 3 h12 80 2 40 18 g 72 g MSA none 130° C. 3 h 7 49 19 41 18 g 180 g MSA none115° C. 24 h 22 78 42 18 g 180 g MSA none 140° C. 3 h 16 69 2 43 18 g180 g MSA none 150-160° C.   2 h 91 44 18 g 90 g MSA none 160° C. 2h >90 45 30 g 300 g MSA none 130° C. 4 h 6 81 1 46 36 g 200 g formicacid none reflux 4 h 100

EXAMPLES 47 TO 65

The following reaction step was also object of further experiments,which are summarized in table 3 below:

TABLE 3 33 g starting material (10) GC [%] Example CH2O solvent acidtemperature time 10 15 16 47 8 g paraformal- none 220 ml TFA reflux 4.5h 97 dehyde 48 8 g paraformal- none 100 ml TFA reflux 4.5 h 99 dehyde 498 g paraformal- none 75 ml TFA reflux 4.5 h 62 32 dehyde 50 8 gparaformal- none 50 ml TFA reflux 4.5 h 62 35 dehyde 51 8 g paraformal-none 50 ml TFA reflux 4.5 h 56 30 dehyde 52 8 g paraformal- none 25 mlTFA reflux 4.5 h 4 32 23 dehyde 53 8 g paraformal- none 100 ml formicacid reflux 4.5 h 9 88 2 dehyde 54 8 g paraformal- none 100 ml propionicacid reflux 4.5 h 56 dehyde 55 8 g paraformal- Cl(CH2)2Cl 1eq. MSAreflux 4.5 h 1 95 dehyde 56 8 g paraformal- Cl(CH2)2Cl 1eq. MSA reflux4.5 h 95 dehyde 57 20 g trioxane none 50 ml TFA reflux 4.5 h 61 25 58 20g trioxane none 50 ml TFA reflux 4.5 h 52 38 59 20 g trioxane none 100ml formic acid reflux 4.5 h 85 12 60 20 g trioxane none 50 ml TFA reflux4.5 h 63 34 61 20 g trioxane none 50 ml formic acid reflux   5 h 15 65 6base solvent 62 4eq. KOH 150 ml ethanol reflux 2.3 h 99 63 4eq. KOH nonereflux 3.5 h 1 97 64 1.5eq. NaOH none 100° C.   5 h 71 23 65 1.5eq. NaOHnone 100° C. 13.5 h  38 49

Besides the variation of solvents, temperatures and other reactionconditions also the educts have been varied as is shown in the followingexamples:

Unless otherwise indicated, materials can be obtained from Aldrich, P.O.Box 2060, Milwaukee, Wis. 53201, USA.

EXAMPLE 66 Preparation of3,4-dihydro-4,4-dibenzyl-2-(3-sulfopropyl)isoquinolinium, Internal salt

Step 1

Preparation of α,α-dibutyl-benzeneacetonitrile (2): To a flame dried 500ml three neck round bottomed flask, equipped with a dry argon inlet,magnetic stir bar, and thermometer, is added benzyl cyanide ((1), 5.0gm.; 0.043 mol) and tetrahydrofuran (100 ml). To the reaction is slowlyadded sodium hydride (60% in oil) (7.2 gm, 0.1075 mol) over one hour.Once addition is complete the reaction is stirred at room temperaturefor 1 hour. To the reaction is added benzyl bromide (18.4 gm; 0.043 mol)and the reaction is stirred at 50° C. for 18 hours. The reaction isevaporated to dryness, residue dissolved in toluene and washed with 1NHCl. Organic phase is dried with Na₂SO₄, filtered and evaporated toyield α,α-dibutyl-benzeneacetonitrile (2), wt=7.7 gm (65%).

Step 2

Preparation of 1-amino-2,2,dibutyl-2-phenylethane (3):α,α-Dibutyl-benzeneacetonitrile ((2), 7.0 gm; 0.0237 mol) is dissolvedin borane-THF complex (1.1 equiv.) at room temperature for 18 hours.Once reaction is complete, ethanol (50 ml) is added, and the reaction isevaporated to dryness. Once dry, the residue is suspended in 100 ml 1MHCl, and the suspension is evaporated to dryness on a rotary evaporator.This procedure is repeated three times. After the final evaporation, thewhite residue is dissolved in 1M NaOH (100 ml), and extracted withdiethyl ether (2×150 ml). The extracts are combined, dried with Na₂SO₄,filtered and evaporated to dryness to yield1-amino-2,2-dibutyl-2-phenylethane (3), wt=6.4 gm (90%).

Step 3.

Preparation of 3,4-dihydro-4,4-dibenzyl-isoquinoline (5): To a flamedried 100 ml three neck round bottomed flask, equipped with an additionfunnel, dry argon inlet, magnetic stir bar, thermometer, Dean Starktrap, and heating bath is added 1-amino-2,2-dibutyl-2-phenylethane ((3),5.0 gm, 0.0166 mol) and toluene (25 ml). To the addition funnel is addedformic acid (5.0 gm). The formic acid is added slowly to the stirringreaction solution over 60 minutes and solids form. Once addition iscomplete the reaction is brought to reflux and water removed via a DeanStark trap. Once the reaction is complete, the toluene is removed toyield N-formyl-β,β-dibutyl-β-phenethylamine (4), wt=4.9 gm (90%). Theformamide (4) is then contacted with polyphosphoric acid (30gm)/phosphorous pentoxide (6 gm), using standard Bischler/Napieralskiconditions, at 170° C. for 18 hours. The reaction is then neutralizedwith aqueous NaOH, keeping the temperature between 60-80° C. Onceneutral, the product is extracted with toluene to yield3,4-dihydro-4,4-dibenzyl-isoquinoline (5). The product can be furtherpurified on silica gel.

Step 4.

Preparation of 3,4-dihydro-4,4-dibutyl-2-(3-sulfopropyl)isoquinolinium,internal salt (6)

To a flame dried 100 ml round bottomed flask is added3,4-dihydro-4,4-di-benzylisoquinoline ((5) 3.0 gm; 0.010 mol) andacetonitrile (25 ml). The solution is stirred at room temperature underargon and to the solution is added 1,2-oxathiolane-2,2-dioxide (1.34 gm;0.011 mol). The reaction is warmed to 50° C. and stirred for 18 hours.The reaction is cooled to room temperature, and allowed to stand at roomtemperature over night. The formed solids are collected by filtration,and washed with chilled acetonitrile, to yield3,4-dihydro-4,4-dibenzyl-2-(3-sulfopropyl)isoquinolinium (6).

EXAMPLE 67 Preparation of3,4-dihydro-4,4-dipentyl-2-(3-sulfopropyl)isoquinolinium, internal salt

The desired product is prepared according to Example 66, substitutingpentyl chloride for benzyl chloride in Step 1.

EXAMPLE 68 Preparation of3,4-dihydro-4,4-dihexyl-2-(3-sulfopropyl)isoquinolinium, internal salt

The desired product is prepared according to Example 66, substitutinghexyl chloride for benzyl chloride in Step 1.

EXAMPLE 69 Preparation of3,4-dihydro-4,4-dibutyl-2-(3-sulfopropyl)isoquinolinium, internal salt

The desired product is prepared according to Example 66, substitutingbutyl chloride for benzyl chloride in Step 1.

EXAMPLE 70 Preparation of3,4-dihydro-4,4-di(2-methylphenylmethyl)-2-(3-sulfopropyl)-isoquinolinium,internal salt

The desired product is prepared according to Example 66, substituting2-methylbenzyl chloride for benzyl chloride in Step 1.

EXAMPLE 71 Preparation of3,4-dihydro-4,4-di(3-methylphenylmethyl)-2-(3-sulfopropyl)-isoquinolinium,internal salt

The desired product is prepared according to Example 66, substituting3-methylbenzyl chloride for benzyl chloride in Step 1.

EXAMPLE 72 Preparation of3,4-dihydro-4,4-di(4-methylphenylmethyl)-2-(3-sulfopropyl)-isoquinolinium,internal salt

The desired product is prepared according to Example 66, substituting4-methylbenzyl chloride for benzyl chloride in Step 1.

EXAMPLE 73 Preparation of3,4-dihydro-4,4-di(cyclohexylmethyl)-2-(3-sulfopropyl)-isoquinolinium,internal salt

The desired product is prepared according to Example 66, substitutingchloromethyl cyclohexane (prepared from cyclohexanemethanol according toCoe et al., Polyhedron 1992, 11(24), pp. 3123-8) for benzyl chloride inStep 1.

EXAMPLE 74 Preparation of3,4-dihydro-4,4-di(phenylmethyl)-2-(3-sulfobutyl)-isoquinolinium,internal salt

The desired product is prepared according to Example 66, substituting1,2-oxathiane-2,2-dioxide for 1,2-oxathiolane-2,2-dioxide in Step 4.

EXAMPLE 75 Preparation of3,4-dihydro-4,4-di(phenylmethyl)-2-[2′-(sulfooxy)ethyl]-isoquinolinium,internal salt

The desired product is prepared according to Example 66, substituting1,3,2-dioxathiolane-2,2-dioxide for 1,2-oxathiolane-2,2-dioxide in Step4.

EXAMPLE 76 Preparation of3,4-dihydro-4,4-di(phenylmethyl)-2-[3-(sulfooxy)propyl]-isoquinolinium,internal salt

The desired product is prepared according to Example 66, substituting1,3,2-dioxathiane-2,2-dioxide for 1,2-oxathiolane-2,2-dioxide in Step 4.

EXAMPLE 77 Preparation of 3,4-dihydro-4,4-di(4-methylphenylmethyl)-7-methyl-2-(3-sulfopropyl)-isoquinolinium, internal salt

Step 1:

Preparation of4-Methyl-α-(4-methylphenyl)-α-[(4-methylphenyl)methyl]-benzenepropanenitrile

Part a.

Preparation of silica catalyst: Silica (MKC-500, specific surface area497 m² g⁻¹; obtained from Nikki Chemical) is activated by treatment with6N HCl and dried in a vacuum at 120° C. A mixture of 7.0 g of activatedsilica gel and 80 ml of toluene is placed in a flask and stirred for onehour. Then, 25 ml of N-(2-aminoethyl)-3-aminopropyltrimethoxysilane(SH-6020; obtained from Troy Silicone) is injected by syringe and theresulting mixture refluxed with an oil bath for 8 h. After cooling, thesilica gel is filtered and washed with benzene in a soxhlet extractorfor 12 h. The purified silica is washed again three times with diethylether and allowed to stand overnight in air. One gram of the purifiedsilica is then suspended in 1.5 ml of dioxane for 8 h, after which 4.3ml of 1,10-dibromodecane is added and the mixture stirred at 80° C.overnight in an oil bath. The silica is then filtered on a glass filterand washed with dioxane, acetone and 1% NH₄OH and subsequently washedwith acetone and diethyl ether. The silica so obtained is dried at 50°C. under reduced pressure overnight.

Part b.

Preparation of4-Methyl-α-(4-methylphenyl)-α-[(4-methylphenyl)methyl]-benzenepropanenitrile:A flask containing 1.0 g (2 mmol) of sodium cyanide (95%) dissolved in 5ml of 50% NaOH aqueous solution is charged with 0.3 g silica catalyst,followed by 4-methylbenzyl chloride (6.8 mmol) and 1 ml toluene. Theflask is placed in an oil bath and heated at 40° C. with stirring for 48h, after which 10 ml toluene is added. The organic layer is filtered andthe filtrate evaporated to yield4-methyl-α-(4-methylphenyl)-α-[(4-methylphenyl)methyl]-benzenepropanenitrile.

Step 2.

Preparation of4-methyl-α-(4-methylphenyl)-α-[(4-methylphenyl)methyl]-benzenepropanamine

The desired product is prepared according to Example 66, Step 2,substituting4-methyl-α-(4-methylphenyl)-α-[(4-methylphenyl)methyl]-benzenepropanenitrilefor α,α-dibutyl-benzeneacetonitrile.

Step 3.

Preparation of3,4-dihydro-4,4-di(4-methylphenylmethyl)-7-methyl-isoquinoline: Thedesired product is prepared according to Example 66, Step 3,substituting4-methyl-α-(4-methylphenyl)-α-[(4-methylphenyl)methyl]-benzenepropanaminefor 1-amino-2,2,dibutyl-2-phenylethane.

Step 4.

Preparation of 3,4-dihydro-4,4-di(4-methylphenylmethyl)-7-methyl-2-(3-sulfopropyl)-isoquinolinium, internal salt

The desired product is prepared according to Example 66, Step 4,substituting3,4-dihydro-4,4-di(4-methylphenylmethyl)-7-methyl-isoquinoline for3,4-dihydro-4,4-di-benzylisoquinoline.

EXAMPLE 78 Preparation of3,4-dihydro-4,4-di(4-iso-propylphenylmethyl)-7-iso-propyl-2-(3-sulfopropyl)isoquinolinium,internal salt

The desired product is prepared according to Example 77, substituting4-iso-propylbenzyl chloride for 4-methylbenzyl chloride.

EXAMPLE 79 Simultaneous Preparation of Organic Catalyst MixtureComprising Catalysts of Formula 3 Wherein R¹ are Independently H,Methyl, Ethyl and Mixtures Thereof

Formula 3

The desired mixture of products is prepared according to Example 77,substituting a mixture of benzyl chloride (source for R¹═H),4-methylbenzyl chloride (source for R¹=methyl), and 4-ethylbenzylchloride (Oakwood Products, Inc., West Columbia, S.C. 29172, USA; sourcefor R¹=ethyl) for 4-methylbenzyl chloride. This results in a mixture of18 distinct organic catalyst compounds.

EXAMPLE 80

The organic catalysts listed below are tested according to Applicants'Organic Catalyst/Enzyme Compatibility Test using [Peracetic Acid]=5.0ppm; [organic catalyst]=0.5 ppm and the following results are obtained.

**Catalyst Moieties Enzyme Compatibility Values Entry* R²; G ECV_(ter)ECV_(dur) ECV_(nat) ECV 1 NA 51 86 58 65 2 NA 54 90 57 67 3 benzyl; —O—101 100 103 101 4 benzyl; —CH₂— 102 99 104 102 5 4-methylbenzyl; 103 9999 100 —CH₂— *Entry 1 and 2 are Sulfuric acidmono-[2-(3,4-dihydro-isoquinolin-2-yl)-1-((1,1-di-methylethoxy)methyl)ethyl]ester, internal salt and Sulfuric acidmono-[2-(3,4-dihydro-isoquinolin-2-yl)-1-(2-ethyl-hexyloxymethyl)-ethyl]ester, internal salt, respectively, which are not encompassed byApplicants' Formulae 1 and 2. **R¹ is H for entries 3-5.

While particular embodiments of the present invention have beenillustrated and described, it would be obvious to those skilled in theart that various other changes and modifications can be made withoutdeparting from the spirit and scope of the invention. It is thereforeintended to cover in the appended claims all such changes andmodifications that are within the scope of this invention.

The invention claimed is:
 1. A process for producing a quaternized sulfogroup-containing 3,4-dihydroisoquinoline, comprising (a) reducing anitrile of a benzyl cyanide, to give an amine; (b) amidifying the amineobtained in the reducing (a), to give an amide; (c) ring closing theamide obtained in the amidifying (b), to give a 3,4-dihydroisoquinoline;and (d) quaternizing the 3,4-dihydroisoquinoline obtained in the ringclosing (c) with a sulfo group-containing compound, to give aquaternized sulfo group-containing 3,4-dihydroisoquinoline, wherein saidsulfo group-containing compound excludes thionyl chloride.
 2. Theprocess of claim 1, wherein the reducing (a) is performed with hydrogenin the presence of a catalyst.
 3. The process of claim 1, wherein theamidifying (b) is performed with at least one selected from the groupconsisting of formic acid and formic acid ester.
 4. The process of claim1, wherein the ring closing (d) is performed with phosphorous pentoxideand an acid.
 5. The process of claim 4, wherein the acid is selectedfrom the group consisting of poly phosphorous acid,trifluoromethanesulfonic acid, formic acid, and methane sulfonic acid.6. The process of claim 4, wherein the reaction mixture of the ringclosing (c) is neutralized with KOH.
 7. The process of claim 1, wherein,in the ring closing (c), after neutralization, the amine is oxidizedwith sodium hypochlorite to give an imine.
 8. The process of claim 1,wherein, in the quaternizing (d), the alkylating agent is employed in anamount of 1 to 1.2 equivalents based on the 3,4-dihydroisoquinoline fromthe ring closing (c).
 9. The process of claim 1, wherein, in at leastone of (a) to (d), a solvent is employed.
 10. The process of claim 9,wherein the same solvent is employed in more than one of (a) to (d). 11.The process of claim 9, wherein the solvent is toluene.
 12. The processof claim 10, wherein the solvent is toluene.
 13. The process of claim 1,further comprising: bisalkylating a benzyl cyanide, to give abisalkylated benzyl cyanide, which bisalkylated benzyl cyanide is thenitrile which is reduced in the reducing (a).
 14. The process of claim13, wherein, in the bisalkylating, at least one selected from the groupconsisting of an alkyl chloride, alkyl bromide, alkyl iodide, alkyltosylate, a substituted aryl chloride, substituted aryl bromide,substituted aryl iodide, and substituted aryl tosylate, is employed inamount of 2 to 4 equivalents based on the benzyl cyanide.
 15. Theprocess of claim 14, wherein in the bisalkylating, at least one selectedfrom the group consisting of an alkyl chloride and a substituted benzylchloride is employed in amount of 2 to 2.5 equivalents based on thebenzyl cyanide.
 16. The process of claim 13, wherein the bisalkylatingtakes place in the presence of 2 to 4 equivalents, based on the benzylcyanide, of a base.
 17. The process of claim 16, wherein the base isKOtBu or KOH/tBuOH.
 18. The process of claim 13, wherein solvent,alkylating agent, and the benzyl cyanide are first mixed, and thebisalkylating is initiated by addition of base.
 19. The process of claim13, wherein, in at least one of the bisalkylating, (a) to (d), a solventis employed.
 20. The process of claim 19, wherein the same solvent isemployed in more than one of the bisalkylating, (a) to (d).
 21. Theprocess of claim 1, wherein the sulfo group-containing compound is1,2-oxathiolane-2,2-dioxide or 1,2-oxathiane-2,2-dioxide.
 22. Theprocess of claim 1, wherein the quaternized sulfo group-containing3,4-dihydroisoquinoline is1-(4,4-dimethyl-3,4-dihydroisoquinoline)decane-2 sulfate.